1. Field of the invention
This invention relates to a process for the purification of steroids such as 19-norethisterone and 19-norandrost-4-ene-3,17-dione.
More particularly, this invention relates to a process for purifying crude 19-norandrost-4-ene-3,17-dione or 19-norethisterone resulting from ethynylation of 19-norandrost-4-ene-3,17-dione so as to free it from such impurities as colored substances, high molecular weight substances, ethynylestradiol, estrone and the like present in the crude product.
2. Description of the Prior Art
19-NORANDROST-4-ENE-3,17-DIONE IS USEFUL AS AN INTERMEDIATE IN THE PREPARATION OF 19-NORETHISTERONE.
19-NORETHISTERONE IS A MEDICAMENT ADMINISTERED TO A WOMAN OVER A LONG PERIOD OF TIME SO THAT IT HAS SEVERE RESTRICTIONS REGARDING PURITY, COLOR, THE NUMBER AND CONTENTS OF CONTAMINANTS, ETC. For example, according to U.S. Pharm. XIX, 19-norethisterone is required to have a purity in the range of 97.0% to 102.0% and to be white or milk white in color and the number of contaminants must be not more than three, each contaminant being present in a proportion of not more than 1%.
The crude 19-norethisterone contains as a contaminant ethynylestradiol which possesses a ovarian hormonal activity and the incorporation of which, therefore, offers a pharmacological and operation-environmental problem.
The commercial purification of 19-norethisterone has heretofore been accomplished by a relatively complicated process comprising stirring it in a reactor together with an adsorbent such as activated carbon, alumina, etc. followed by filtration and repeated crystallization. However, the recovery of pure product attained according to this process is low and it is hard to say that this process is well suited for the processing of large amounts of 19-norethisterone.
The crude 19-norethisterone resulting from the ethynylation of 19-norandrost-4-ene-3,17-dione also contains a considerably wide variety of impurities, which are difficult to be removed by means of repeated crystallization from various solvents. Moreover, if ethynylestradiol and similar contaminants are to be removed completely, the recovery of pure 19-norethisterone will be so low as to be inadequate for commercial-scale purification.
The use of conventional adsorbents such as activated carbon, silica gel, ion-exchange resins and the like enables such contaminants as colored substances, polar substances, high polymers, etc. to be removed appreciably, but those substances having rather small polarity do not tend to be removed with such an absorbent.
Among these absorbents, silica gel, neutral or acidic alumina, basic alumina calcined at a relatively low temperature, activated carbon and the like can be used to remove ethynylestradiol to some extent, but suffer from a disadvantage that complete removal of ethynylestradiol is attained only at the cost of a decreasing recovery of the desired 19-norethisterone.
Basic ion-exchange resins permit selective removal of ethynylestradiol, but they also involve a disadvantage that the other contaminants are scarcely removed therewith.